Polymeric prodrugs with precisely controlled drug loading content (DLC) and rapid intracellular destabilization generally require complicated chemistry that hinders large-scale manufacture. For this purpose, we reported in this study a facile construction of reduction-sensitive amphiphilic polyprodrugs with an anticancer drug, 10-hydroxycamptothecin (HCPT), and a hydrophilic poly(ethylene oxide) (PEG) moiety as the alternating building blocks of the multiblock copolymer using Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAc) click coupling between azide-SS-HCPT-SS-azide and alkyne-PEG-alkyne. Adoption of PEGs with two different molecular weights (MWs) of 400 and 1450 Da (PEG400 and PEG1450) afforded two polyprodrugs with different DLCs. Both formulations can self-assemble into spherical micelles with hydrodynamic diameter smaller than 200 nm, and exhibit glutathione (GSH)-triggered degradation for promoted drug release. A further comparison study revealed that the PEG1450-based polyprodrug is a better formulation than the analogue constructed from PEG400 in terms of in vitro drug release behaviors, and cytotoxicity. This work thus provides a facile yet efficient strategy toward polymeric prodrugs with precisely controlled DLC and reduction-triggered degradation for enhanced anticancer drug delivery.

中文翻译：

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具有精确定制的药物负载量以控制释放的10-羟基喜树碱骨架两亲多前药的简便制备

具有精确控制的药物装载量（DLC）和快速的细胞内去稳定作用的聚合物前药通常需要复杂的化学反应，这阻碍了大规模生产。为此，我们在本研究中报道了一种具有抗癌药，10-羟基喜树碱（HCPT）和亲水性聚环氧乙烷（PEG）部分作为多嵌段交替结构单元的还原敏感性两亲性前药的简便构建方法。铜（I）催化的叠氮化物-炔烃环加成反应（CuAAc）的共聚物在叠氮化物-SS-HCPT-SS-叠氮化物和炔烃-PEG-炔烃之间的点击耦合。两种具有400和1450 Da的不同分子量（MW）的PEG（PEG400和PEG1450）的采用提供了两种具有不同DLC的多药前药。两种配方均可自组装成流体动力直径小于200 nm的球形胶束，并表现出谷胱甘肽（GSH）触发的降解，以促进药物释放。进一步的比较研究表明，就体外药物释放行为和细胞毒性而言，基于PEG1450的多前药比从PEG400构建的类似物更好。因此，这项工作为聚合物前药提供了一种简便而有效的策略，该聚合物前药具有精确控制的DLC和减少触发的降解作用，从而增强了抗癌药物的传递能力。